Conditioning Regimen For Stem Cell Transplantation Research Articles

Antiemetic prophylaxis regimens in haematologic malignancies patients undergoing a hematopoietic stem cell transplantation. Which is the best standard of care? A systematic review.

This systematic review, adhering to PRISMA guidelines, aimed to evaluate the efficacy and safety of antiemetic prophylaxis in haematological patients undergoing high-dose chemotherapy as part of their hematopoietic stem cell transplantation (HSCT) conditioning regimens. We performed a comprehensive search in PubMed, EMBASE, ClinicalTrials.gov and the Cochrane database to identify randomised controlled trials (RCTs) and systematic reviews of antiemetic prophylaxis. Studies in English, French, Italian or Spanish were included. This review is registered with PROSPERO, ID CRD42023406380. Eight RCTs were analysed. The antiemetic regimens evaluated ranged from monotherapy with 5-Hydroxytryptamine Receptor 3 antagonists (5-HT3RAs) to complex combinations including olanzapine, neurokinin-1 receptor antagonists, 5-HT3RAs and corticosteroids. Complete response rates for triplet or quadruple regimens varied between 23.5% and 81.9%. Although no significant adverse effects were observed, minor symptoms such as diarrhoea, constipation, sedation and headaches were reported. Existing evidence on HSCT antiemetic therapy highlights its benefits but fails to provide clear clinical directions. The choice between triplet and quadruplet therapies for different patient scenarios is still uncertain. Until more detailed research is available, healthcare providers must rely on the latest guidelines and their judgement to customise antiemetic care for each patient's specific needs and risks.

Autologous hematopoietic stem cell transplantation conditioning regimens and chimeric antigen receptor T cell therapy in various diseases.

Conditioning regimens employed in autologous stem cell transplantation have been proven useful in various hematological disorders and underlying malig nancies; however, despite being efficacious in various instances, negative consequences have also been recorded. Multiple conditioning regimens were extracted from various literature searches from databases like PubMed, Google scholar, EMBASE, and Cochrane. Conditioning regimens for each disease were compared by using various end points such as overall survival (OS), progression free survival (PFS), and leukemia free survival (LFS). Variables were presented on graphs and analyzed to conclude a more efficacious conditioning regimen. In multiple myeloma, the most effective regimen was high dose melphalan (MEL) given at a dose of 200/mg/m2. The comparative results of acute myeloid leukemia were presented and the regimens that proved to be at an admirable position were busulfan (BU) + MEL regarding OS and BU + VP16 regarding LFS. In case of acute lymphoblastic leukemia (ALL), BU, fludarabine, and etoposide (BuFluVP) conferred good disease control not only with a paramount improvement in survival rate but also low risk of recurrence. However, for ALL, chimeric antigen receptor (CAR) T cell therapy was preferred in the context of better OS and LFS. With respect to Hodgkin's lymphoma, mitoxantrone (MITO)/MEL overtook carmustine, VP16, cytarabine, and MEL in view of PFS and vice versa regarding OS. Non-Hodgkin's lymphoma patients were administered MITO (60 mg/m2) and MEL (180 mg/m2) which showed promising results. Lastly, amyloidosis was considered, and the regimen that proved to be competent was MEL 200 (200 mg/m2). This review article demonstrates a comparison between various conditioning regimens employed in different diseases.

Determination of Busulfan and Melphalan in Plasma by Turbulent Flow Chromatography-Tandem Mass Spectrometry.

Melphalan and busulfan are DNA-alkylating agents that are often used concurrently in hematopoietic stem cell transplant (HCT) conditioning regimens. Studies have demonstrated that this combination of alkylating agents is very effective and well-tolerated prior to HCT. This combination is widely used for acute leukemia, advanced lymphoid malignancies, and multiple myeloma. Our goal was to develop an assay for the rapid measurement of both compounds simultaneously in the hopes that rapidly measuring their concentrations could possibly shorten the length of hospital stay. It would also simplify specimen handling in the clinic and the laboratory, reduce the amount of blood drawn, and allow for rapid reporting of the drug levels, thereby facilitating rapid dose adjustments.This chapter describes a validated method that measures both compounds simultaneously. Melphalan and busulfan were extracted from plasma with methanol containing deuterated internal standards. Turbulent flow chromatography coupled with reversed-phase HPLC was used for separation, while the mass spectrometer was set in the positive ion mode. This method has proven accurate and rapid and allowed for timely dose adjustments. The assay was linear over the clinically relevant ranges; the analytical measurement range for busulfan and melphalan was 10-5000ng/mLand 10-15,000 ng/mL, respectively. Specimens containing elevated drug levels were diluted yielding a final clinically reportable range of 10-25,000ng/mL for busulfan and 10-75,0000ng/mL for melphalan. This method is very suitable for simultaneous measurements of these drugs and is currently being used to support pharmacokineticstudies.

Going Going Gonad: Assessing Iron Staining Impact on Fertility for Patients with Sickle Cell Disease

Introduction: Medical advances in the care of patients with sickle cell disease (SCD) and other hemoglobinopathies have allowed for the focus of care to shift and incorporate long-term quality of life metrics, such as fertility. Concerns for reproductive health in patients with SCD stem from the underlying disease itself as well as from medical therapies that are offered such as hydroxyurea, chronic red blood cell transfusions, and stem cell transplant (SCT). Iron deposition from chronic transfusions in other tissues is known to result in end organ damage and lifelong consequences. While little is known about iron overload and fertility, one study noted testicular iron deposition on MRI in pubertal males with transfusion-dependent beta-thalassemia; results were notable for lower sperm concentrations and a lower percentage of sperm with normal morphology, indicating that iron overload likely has an impact on fertility for patients. Iron deposition has not been studied in the pre-pubertal hemoglobinopathy population. Fertility counseling in this patient population does not often occur until patients are considering SCT as a curative therapy option, as the conditioning regimens for SCT are gonadotoxic. Without a good understanding of the impact of chronic transfusions on fertility for patients with hemoglobinopathies, it is difficult to determine the optimal time to offer fertility preservation to families. We aim to assess iron overload on testicular tissue to gain a better understanding of the impact that medical management and chronic transfusions can have on fertility for a patient with SCD. Methods: Our study is a cross-sectional evaluation of patients with SCD who underwent testicular tissue cryopreservation (TTC) as a part of a multicenter research protocol through the University of Pittsburgh Medical Center (UPMC) prior to SCT. As part of the TTC protocol, each patient provided a small piece of tissue for research, with the remaining cryopreserved for patient use. All samples were evaluated for the presence of germ cells. For this study, demographics, treatment data, imaging results, and labs pertinent to hormonal profile and iron status were obtained. All samples from patients with SCD and thalassemia will undergo additional pathology review to evaluate for the presence of germ cells and iron. At the time of this abstract, the tissue for two patients had been analyzed. Results: Banked research tissue from UPMC includes 77 patients with SCD and 21 patients with beta thalassemia major. Of the 77 SCD patient samples, 42 were found to have germ cells, 34 have not yet been analyzed and 1 had no germ cells present. Of the 21 samples from patients with beta thalassemia major, 17 were found to have germ cells, 3 were not yet analyzed and 1 had no germ cells present. To date, we have obtained pathology review on two patients, both with Hb SS genotype and were on the maximum tolerated dose of hydroxyurea prior to TTC. Patient 1 had been on hydroxyurea for 7 years and had 13 units of blood transfusions, and Patient 2 on hydroxyurea for 4 years and 6units of blood transfusions prior to TTC. Both patients were found to have normal testicular tissue histopathology with presence of germ cells and without evidence of iron on staining (Table 1). Conclusions: Based on our preliminary data it can be noted that patients without significant iron burden, based on low ferritin and a limited transfusion history may not have a significant impact on their testicular histopathology with their iron staining being negative. We will expand our patient cohort to include patients who have a severe disease course requiring more blood transfusions to determine whether this is associated with increased iron deposition in their testicular tissue and/or reduced germ cell numbers. This information will allow teams to optimize the timing of fertility discussions and possible preservation in this patient population, even outside of curative treatment.

Stem cell transplantation patients receiving a novel oral care protocol for oral mucositis prevention and treatment: patient-reported outcomes and quality of life

BackgroundOral mucositis (OM) is one of the most debilitating effects of toxicity due to hematopoietic stem cell transplantation (HSCT) conditioning regimens. The aim of this secondary analysis of the data of a phase II study designed to assess the efficacy of a novel oral care protocol containing bovine colostrum and aloe vera to prevent oral mucositis was to compare outcomes reported by patients with those collected by healthcare professionals (HCPs).MethodData on oral mucositis severity, duration, time of onset and related pain were collected from patients using the Oral Mucositis Daily Questionnaire (OMDQ). HCPs assessed the same outcomes using the World Health Organization oral mucositis scale and pain numerical rating scale. Quality of life was assessed with the 3-level EuroQol-5 dimensions.ResultsFifty-nine autologous/allogeneic graft patients were recruited, 46 of whom (78.0%) experienced OM. Mean onset was 9.1 (SD ± 3.5) days after conditioning initiation, mean duration was 10.4 (SD ± 4.3) days, and the average maximum pain score was 3.7 (SD ± 2.7). Self-administration of the OMDQ detected oral symptoms at least 1 day sooner compared to objective assessments (p = 0.025). Significant differences were observed between the patient-reported and the HCP-assessment data on oral mucositis severity grading distribution (p < 0.0001) and highest pain score (p < 0.0001). Quality of life score variations were correlated with changes in oral mucositis severity during patients’ hospital stay.ConclusionsFurther studies are necessary to improve the understanding of these findings; a randomised controlled trial is being set up at our institution.

Guillain-Barré Syndrome after Hematopoietic Transplantation

The Hematology Service at the University Hospital of Federal University of Juiz de Fora (HU-UFJF)/Brazil carried out a research project focused on assessing the toxicity and effectiveness of progressive Lomustine doses in association with Etoposide and Cyclophosphamide in the Autologous Hematopoietic Stem Cell Transplantation (AHSCT) conditioning regimen adopted for lymphoma patients. During the follow-up, a 31-year-old woman belonging to the 400 mg/m2 Lomustine cohort evolved with neuromuscular complications 6 months after AHSCT. Initially, she experienced diffuse pain, mainly proximal weakness in the lower limbs; however, it got worse 10 days after vaccine protocol application. She evolved with rapidly ascending motor worsening, decreased ability to walk, foot paresthesia, binocular diplopia, areflexia, bulbar and dysautonomic symptoms such as sweating, tachycardia and postural hypotension. She experienced syncope episodes 72 h before being referred to intensive care unit at HU-UFJF.

1163. HIV-1 NAAT Pitfalls in B-cell Lymphoblastic Leukemia Patients Following CAR-T Cell Therapy

BackgroundCAR-T Cell Therapy is approved for the treatment of pediatric patients with relapsed/refractory B-ALL. Lentiviral vector technology, highly modified from HIV-1, is used to induce stable, long-term transgene expression by integration into the host genome. This integration may interfere with HIV-1 NAAT producing false-positive results. MethodsA retrospective chart review of Pre-B ALL patients who underwent to CAR T cell therapy with KYMRIAH(tisagenlecleucel) at a single institution between January 2019 and May 2021 to assess for patients whose CAR-T infusion interfered with post-infusion HIV-1 testing. All patients had HIV NAAT pre and post CAR T-cell therapy (using platform, Roche COBAS AmpliPrep/Quantitative TaqMan HIV-1 T). Reactive HIV NAAT by Roche test were subsequently tested using different HIV-1 assay platforms to rule out or confirm HIV infection.ResultsWe report three cases in which interpretation of HIV-1 NAAT testing was complicated by CAR T cell therapy. Case 1: 1-year-old male with refractory infantile leukemia was found to have a reactive HIV NAAT post CAR-T in routine infectious screening prior to SCT. Case 2: 3-year-old refractory ALL planned for SCT who had a reactive HIV NAAT 9 months post CART. Fourth-generation HIV-1 testing (targeting the p24 antigen and anti-HIV-1 antibodies) was negative pre and post CART. Viral loads were also undetectable indicating false-positive post-CAR-T HIV-1 NAT test results. Case 3: 21-year-old sexually active female with relapsed B cell ALL. Post CAR-T HIV NAAT was reactive, and a quantitative viral load was positive at 176 copies/mm3 one day prior to start of stem cell transplant conditioning regimen. Aptima HIV testing is typically used as confirmatory test for CAR-T associated false positive HIV NAT cases, but surprisingly, the Aptima test was also reactive. Additional testing with Abbott m2000 Realtime HIV-1 assay and 4th generation p24 antigen-based testing were both negative. Table 1 Summary of reported patients with false-positive HIV-1 NAAT test results following CAR T cell therapy and Table 2, HIV platforms used for screening and diagnosis with interpretations following CAR T cell therapy.ConclusionClinicians need to be aware of potential false-positive HIV testing after CAR-T therapy. HIV testing platforms with targets not used in lentiviral vectors (4th generation test/P24, or Abbott test/integrase region) are highly recommended to avoid delays in subsequent therapy and unwanted stress for the patients, families, and cliniciansDisclosures All Authors: No reported disclosures

Alemtuzumab clearance, lymphocyte count, and T‐cell chimerism after hematopoietic stem cell transplant in sickle cell disease

AbstractStudy ObjectiveAlemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such as chronic lymphocytic leukemia, and incorporated into many hematopoietic stem cell transplant (HSCT) conditioning regimens, few studies have evaluated the pharmacology of alemtuzumab in adult patients with sickle cell disease (SCD). We therefore examined the pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab in adults with SCD who received a matched related donor HSCT to determine if the clearance of alemtuzumab affects transplant outcomes.DesignPK and PD analysis of patient data from a single‐center clinical trial.SettingClinical research center.PatientsTwenty‐two adult patients with SCD who received one of two nonmyeloablative allogeneic HSCT regimens: alemtuzumab and total body irradiation (Alem‐TBI) or pentostatin, cyclophosphamide, alemtuzumab, and total body irradiation (Pento‐Cy‐Alem‐TBI).Measurements and Main ResultsAlemtuzumab serum concentrations, absolute lymphocyte counts, T‐cell (CD3), and myeloid (CD14/15) chimerism were collected at distinct time points and analyzed. A semi‐mechanistic PK population model was built to understand inter‐individual differences in pharmacology. Alemtuzumab was detectable up to 28 days post‐HSCT. The mean alemtuzumab level 7 days after transplant for patients on Alem‐TBI was 818 ng/ml, significantly lower than the mean level of 1502 ng/ml for patients on Pento‐Cy‐Alem‐TBI (p &lt; 0.001), but this difference decreased as time progressed. The clearance of alemtuzumab was linear, and the half‐life was longer in the Pento‐Cy‐Alem‐TBI group (average half‐life = 61.1 h) compared to the Alem‐TBI group (average half‐life = 44.1 h) (p &lt; 0.001). The CD3 chimerism at 2 and 4 months after transplant positively correlated with alemtuzumab levels collected on day 14 after transplant (R2 = 0.40 and p = 0.004 at 2 months, R2 = 0.36 and p = 0.005 at 4 months), but this significance was lost by 6 months after HSCT. No correlation was seen between alemtuzumab levels and CD14/15 chimerism.ConclusionBetween 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment, suggesting more lymphodepletion may be needed to reduce graft failure in these two non‐myeloablative matched related donor HSCT regimens.

Thiotepa, Busulfan, and Cyclophosphamide and Busulfan, Cyclophosphamide, Etoposide As Autologous Stem Cell Transplantation Conditioning Regimen in Primary Central Nervous System Lymphoma

IntroductionPrimary central nervous system lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma and standard treatment is yet to be established. Induction therapy with methotrexate-based chemotherapy regimen and consolidation with high-dose chemotherapy followed-by autologous stem cell transplantation (ASCT) is a good treatment option with promising outcomes, but only few studies are available. Asan Medical Center had previously used busulfan, cyclophosphamide, and etoposide regimen (BuCyE) as standard high-dose chemotherapy in consolidation therapy until thiotepa, busulfan, and cyclophosphamide regimen (TBC) was introduced in December, 2012. The purpose of this study is to compare outcomes and toxicity profile of BuCyE and TBC as conditioning regimens for ASCT in consolidation therapy of PCNSL patients.MethodsThe registry data set of PCNSL, collected from March 1993 to May 2017 at a single institute, Asan Medical Center, was retrospectively reviewed and patients who had BuCyE or TBC as conditioning regimens were enrolled in analyses. BuCyE group had busulfan with dose of 3.2 mg/kg IV in day-7 to day-5, etoposide 200 mg/ IV in day-5 to day-4 and cyclophosphamide 50 mg/kg IV in day-3 to day-2. TBC group had thiotepa with dose of 250 mg/ IV in day-9 to day-7, busulfan 3.2 mg/kg IV in day-6 to day-4 and cyclophosphamide 60 mg/kg IV in day-3 to day-2. OS was defined as from beginning of high-dose chemotherapy conditioning to any cause of death, and PFS as from beginning of ASCT to disease progression or any cause of death. Analyses with chi-square test or Fisher's exact test were done to compare variables between two groups. Survival curves were estimated by Kaplan-Meier methods with log-rank tests and multivariate analyses were done with known prognostic factors. All statistical analyses were performed using IBM SPSS version 21.0.ResultsTotal 241 patients with diagnosis of PCNSL were identified and 73 patients who had ASCT as frontline or salvage setting with conditioning regimens of either TBC (45 patients) or BuCyE (28 patients) were enrolled in analyses. Median follow-up duration was 3.7 years [IQR 0.01-10.3], median OS was 6.1 years [95% CI 3.7-8.5], and median PFS was 6.5 [95% CI 1.4-11.7]. Median age was 54 years (range, 17-65), 27.4% of patients were 60 years or older and 54.8% of patients was male. Fifty three patients (72.6%) had upfront ASCT after induction therapy and 27.4% of patients had relapsed or refractory disease. ECOG performance status and infused dose of CD34 positive cells showed no statistical difference between two groups. Proportion of patient with refractory or relapsed disease was significantly higher in TBC group [TBC 37.8%, BuCyE 10.7%, p = 0.012]. Median OS of TBC group was not reached and median OS of BuCyE group was 4.5 years [95% CI 1.8-7.2] and TBC group showed better OS with log-rank test (p = 0.048). Median PFS of TBC group was not reached and median PFS of BuCyE group was 1.3 years [95% CI 0.00-2.7] and TBC group showed better PFS with log-rank test (p = 0.007). In multivariate analyses with age, ECOG performance status, CSF protein level, serum LD level, TBC group showed significantly better OS with HR of 0.20 [95% CI 0.04-0.97, p = 0.046] and better PFS with HR of 0.24 [95% CI 0.09-0.66, p = 0.006] compared to BuCyE group. Severe oral mucositis, nausea, vomiting (NCI CTC grade 3 or 4) was higher in TBC group. Median days to engraftment were 8 days (range, 3-19) in TBC group, and 9 days (range, 3-15) in BuCyE group. Median admission duration was 17 days (range, 4-42) in TBC group, and 18.5 days (range, 14-36) in BuCyE group. One case of treatment-related mortality was reported in TBC group due to septic shock.ConclusionTBC regimen showed better outcomes in both OS, PFS compared to BuCyE. Although TBC group showed more oral mucositis, nausea, vomiting, and diarrhea, it maybe tolerable regimen compared with BuCyE considering the fact that admission duration and days to engraftment was not inferior. Further long-term follow-up results with TBC regimen are warranted. DisclosuresNo relevant conflicts of interest to declare.

Pilot Study of Safety and Efficacy of Chidamide in Allogenic Peripheral Hematopoietic Stem Cell Transplantation: Better Disease Control and Positively Lower Graft Versus Host Disease

IntroductionThe combination of busulfan (Bu) and fludarabine (Flu) is an effective and well-tolerated hematopoietic stem cell transplantation (HCT) conditioning regimen for patients with acute leukemia. However, relapse remains the main reason for treatment failure. Increasing intensity of conditioning therapy leads to not only better control of disease, but more treatment related mortality including graft versus host disease (GVHD). Song and Partow demonstrated that introducing histone deacetylase inhibitor (HDACi) vorinostat into busulfan/fludarabine/clofarabine (Bu/Flu/Clo) could augment disease control in vitro and in vivo, without increasing toxicity. Pavan and Choi showed vorinostat decrease GHVD while preserving graft versus leukmia effect. We conducted a clinical trial to evaluate the role of a selective HDACi chidamide in allogenic HCT.MethodsChidamide was given orally twice weekly at dose of 20 mg from day -7 to 2 weeks post transplantation. Busulfan was administered intravenously at fixed dose of 3.2 mg/kg for 4 days from day -6 to -3. Fludarabine and cytarabine were given intravenously at dose of 30 mg/m2 and 1g//m2 respectively for 5 days from day -6 to -2. GVHD prophylaxis was based on post-transplantation cyclophosphamide (50 mg/kg on day +3, +4) and cyclosporine started from day +5. The presence of minimal residual disease (MRD) was determined by multi-parameter flow cytometry.ResultsForty patients (24 AML, 6 MDS, 10 ALL) with median age 41 years (range 16-60) received an allogeneic matched sibling (n=34) or unrelated donor (n=6) HCT in CR1 (n=15), CR2 (n=6), with residual disease (n=10), or with active disease (n=9). Seventeen patients had adverse risk karyotype according to European LeukemiaNet risk stratification. Median time to ANC > 0.5 x 109/L and platelets > 20 x 109/L were 16 (range 9-36) and 18 days (11-44), respectively. Short-term (before recovery of ANC and platelets) adverse events included neutropenic fever (80%), reversible grade 2 elevation of liver enzyme (42.5%), and grade 2 mucositis (27.5%). Median follow-up time of the whole cohort was 11.5 months (3-24.7). All patients achieved CR and clearance of MRD by day +30 after HCT. All patients achieved 100% donor chimerism at 30 days following HCT. The incidence of grades II-IV and grade III-IV acute GVHD is 11% and 5% respectively. Only one patient died of aGVHD. Chronic extensive GVHD among 38 evaluable patients is 9%. Median follow-up time of the whole cohort is 11.5 month (3-24.7). Estimated progression free survival and overall survival at 1 year are 75% and 84.6% respectively (Figure1-A). Patients with MRD have inferior survival compere with patients without MRD (81.2% vs 68% p=0.336) (Figure 1-B).ConclusionShort-term results indicate introducing chidamide into allogeneic HCT could lead to better control of disease and possible lower GVHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Long-Term Results of Brentuximab Vedotin in Relapsed and Refractory Hodgkin Lymphoma: Multi-Center Real-Life Experience

Introduction:In classical Hodgkin lymphoma (cHL), approximately a third of patients will relapse after first-line therapy and 15% will fail both first and second line therapies, and therapeutic options are still quite limited in these patients. Several studies have shown the efficacy of BV in relapsed/refractory HL patients .We previously reported the primary results of 58 named patient program (NPP) patients, with an objective response rate (ORR) of 63.5% (CR rate: 26.5%) . Here we present the long-term results of cohort (Salihoglu et al. Ann Hematol 2015).Design and Methods:Eleven Turkish institutions participated in this multicenter, retrospective study. Patients were included without any limitations regarding performance status and organ function. All of the patients provided written informed consent. BV is imported via the named-patient-program. BV was given at approved standart dosage.Results:From March 2011 to July 2013, 58 patients were included in the named patient program (table 1) and they were treated with BV and followed-up until July 2017, 4 years after the last time of initiation of BV. Ten patients remained in remission (8 CRs and 2 PRs) without the initiation of new therapy other than stem cell transplantation (SCT). These 10 patients has a median observation time of 54.5 months (range: 10-64 months) and the median observation time for all patients from the first dose was 18.5 months (range: 4-66 months). The median OS and PFS were 19 months (95% CI:0.37-0.63) and 5.5 months (95% CI:0.34-0.59), respectively. The estimated 5-year OS and PFS rates were 25% (95% CI:0.15-0.37) and 12% (95% CI:0.03-0.27), respectively (Table 2; Figure 1 A&B).Among our cohort, 36 (62%) received ≥1 anticancer therapy following BV. Twenty-four patients had SCT following BV treatment; 3, 11, and 8 auto-, allo-, and haplo-SCTs were performed, respectively; and 2, 4, 2 patients received auto-, allo- and haplo-SCT as consolidative therapy following BV, respectively. One and 1 patient received allo- and haplo-SCT as second-line treatment subsequent to BV, respectively. Excluding SCT conditioning regimens; 14 and 10 patients received single and multi agent therapy following BV, respectively. Excluding consolidative SCT, median numbers of subsequent treatments was 1 (range: 1-5).Eighteen of 58 patients (31%) achieved a CR during the follow-up, and better survival outcomes were observed in this group. The median of duration of response was 42 months (range: 2-59 months). The estimated 5-year OS and PFS rates were 59% (95% CI:0.33-0.79) and 34% (95% CI:0.07-0.63), respectively (Figure 1 C&D).Among 15 patients that were in remission at the time of analysis, of 7 patients that remained in the follow-up and in remission, three had consolidative SCT (1 auto- and 2 allo-SCTs) and 4 received no further cancer treatment (22% of all CR patients). Additionally, we should state that one patient, who received no further treatment after BV and who was in CR, died due to lung cancer an 41st month of follow-up.Of the 18 patients who achieved CR after BV, six patients had a consolidative SCT as their next therapy following BV (2 auto-, 3 allo- and 1 haplo-SCT). Additionally, one CR patient underwent haplo-SCT after having had progressive disease. Among 6 patients that had consolidative SCT following achievement of CR, the estimated 5-years OS and PFS rates were 67% (95% CI:0.19-0.90) and 67% (95% CI:0.19-0.90), respectively. For the resting 12 CR patients, the estimated 5-years OS and PFS rates were 55% (95% CI:0.23-0.78) and 41% (95% CI:0.12-0.69), respectively. Among 6 patients who had undergone consolidative SCT, 3 are alive and 3 are dead due to relapsed lymphoma. Of 12 patients who had not received consolidative SCT, five were dead at the time of analysis (Figure 1 E&F).A total of 381 adverse events (AEs) were observed in 49 patients (85%). In general the treatment was well tolerated with dose reduction required in 8 patients (3 due to cytopenias, 1 neutropenia, 1 renal failure, 1 peripheral neuropathy, 2 unknown).In our cohort, we report that 10 patients (17%) had long term continuous response following BV therapy and 5 patients (8.6%) had long term continuous CR (median OS: 56 months; range: 41-64 months) without any additional consolidative therapy. Our results are close to the long term results of pivotal study (Chen et al. Blood 2016) and French study (Perrot et al. Haematologica 2016). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Nonmyeloablative Allogeneic Stem Cell Transplantation with or without Inotuzumab Ozogamicin for Lymphoid Malignancies

Nonmyeloablative Allogeneic Stem Cell Transplantation with or without Inotuzumab Ozogamicin for Lymphoid Malignancies

Neuroprotective Efficacy of Prophylactic Antiepileptic Therapies in Busulfan Conditioning Regimen

AbstractBusulfan (BU) is commonly used in the anticancer treatment and bone marrow/hematopoietic stem cell transplantation (BM/HSCT) conditioning regimen. This study aimed to evaluate the neuroprotective efficacy of antiepileptic therapies in the BU conditioning regimen. Patients who underwent BM/HSCT between January 1, 2009, and January 1, 2014, were evaluated retrospectively. Diagnosis, demographic characteristics, neurological side effects, electroencephalography (EEG) abnormalities, and antiepileptic drugs were determined. Levetiracetam was given to 49% and phenytoin to 23% of patients as antiepileptic prophylaxis. After BU treatment, seizures developed in three patients, posterior reversible leukoencephalopathy in two patients, and peripheral neuropathy in two patients. Forty-five patients who underwent EEG before and after BU treatment were identified. The effects of antiepileptic prophylaxis over the electroencephalographic abnormalities after the BU conditioning regimen were found to be not different (p = 0.491). Neurological side effects and electroencephalographic abnormalities following BU conditioning regimen under antiepileptic prophylaxis are comparable.

Reasearch progress of conditioning regimens for autologous hematopoietic stem cell transplantation in patients with lymphoma

Lymphoma is a malignant tumor with high heterogeneity. Chemoradiotherapy alone is not sufficiently effective for highly invasive lymphomas. Autologous hematopoietic stem cell transplantation(auto-HSCT) plays an important role in the first-line treatment of patients with invasive lymphomas, which can improve the the efficacy of such patients.The common conditioning regimens are high-dose chemotherapy with or without total body irradiation(TBI) in lymphoma patient before auto-HSCT. The clinical usage of these conditioning regimens were limited due to the complications and poor patient tolerance.Therefore, various improved conditioning regimens emerged based on above regimens and the participation of targeted drugs are hot topics in current research.This article summarize the efficacy, toxicity and research advances of conditioning regimens for auto-HSCT in lymphoma. Key words: Lymphoma; Transplantation conditioning; Transplantation, autologous; Hematopoietic stem cell transplantation; Molecular targeted therapy

Logistical Considerations Related to Melphalan As a Conditioning Agent in Autologous Stem Cell Transplant for Multiple Myeloma: Results of a Survey of Oncology Pharmacists, Nurses and Pharmacy Technicians

Introduction: Melphalan is often part of the standard conditioning regimen for autologous stem cell transplantation (SCT) for multiple myeloma (MM). Due to the short stability time for IV admixtures of traditional propylene glycol-containing melphalan products, careful alignment is required between pharmacy, nursing, and patients to ensure timely dose delivery. Propylene glycol-free (PGF) melphalan (Evomela®) has improved stability that may allow for greater medical staff flexibility for scheduling, reconstitution, admixture delivery, and infusion to patients. The aim of this study was to document the steps, time and resource burden incurred when preparing generic propylene glycol containing melphalan and estimate the benefits of stable PGF melphalan. Methods : A survey was conducted with healthcare providers (HCPs) specializing in the care and management of MM patients. HCPs (5 oncology pharmacists, 5 oncology nurses, 5 oncology pharmacy technicians) included those involved in the preparation, administration and monitoring of melphalan when used as a conditioning agent for SCT. HCPs were selected based on a purposeful sampling design to capture a geographically representative sample among US SCT centers. Part 1 of survey consisted of an exploratory qualitative interview with each HCP to capture insights on preparing oncology treatments for administration as well as melphalan-specific insights related to preparation, administration and monitoring. Part 2 of the survey consisted of a quantitative evaluation based on the insights from part 1 of the survey. The quantitative portion focused on capturing facility characteristics as well as melphalan utilization patterns as well as timing and resource consumption related to the preparation, administration, and monitoring of generic melphalan. Additionally, HCPs provided their attitudes towards the potential time benefits of a more stable form of melphalan as it relates to alignment between the pharmacy and the nurses managing the patients during treatment with melphalan. Results are presented as descriptive statistics with mean and standard deviation for continuous variables and counts and percentages for categorical variables. Results: Sixty percent of those surveyed utilized generic melphalan. The steps involved in the preparation of melphalan (generic or PGF) included 1) verification of melphalan prescription, 2) preparation and release of melphalan admixture, 3) delivery of melphalan to the floor, 4) preparation of the patient for administering melphalan, 5) setup and verification of the melphalan pump and administration, and 6) patient monitoring during administration. The total time from start to finish averaged 75.3 (standard deviation: 46.7) minutes (min). The total time spent varied, but the cumulative total time spent incurred across all provider average times was 108.2 min (Table 1). On average, the time of 2.1 pharmacists, 0.9 technicians and 1.5 nurses were utilized in the preparation, administration and monitoring of a melphalan prescription (Table 1). Forty percent of those surveyed had changed from generic to PGF melphalan for the following reasons: convenience for a more stable product (61.5%); convenience for pharmacy preparation planning (46.2%); convenience for patient scheduling (38.5%); improved safety for staff rushing due to risk of precipitation (30.8%); and to reduce the risk of lost treatment due to precipitation (15.4%). HCPs also estimated the potential time benefits of PGF melphalan, which included reducing preparation time by a mean of 4.96 min for pharmacy and nurse alignment to initiate preparation, 3.77 min for pharmacy and nurse to align on pick up, 8.34 min due to nurse time waiting to pick up and 9.77 min for the pharmacy technician or runner to deliver directly to the floor. Conclusions: In this survey of healthcare providers involved in the preparation, administration and monitoring of melphalan as a conditioning treatment for SCT among MM patients, the total time spent was ~1.8 hours for preparing generic melphalan with a potential opportunity to reduce the time by ~0.45 hours when using a PGF melphalan. There may be a potential time and convenience benefit to oncology pharmacists, technician and nurses. Future comparative effectiveness research is needed to confirm these findings in a larger sample of SCT centers using melphalan as a conditioning regimen for SCT among MM patients. Disclosures Acosta: Acrotech Biopharma: Employment. Darban:BluePath Solutions: Consultancy. Gitlin:BluePath Solutions: Consultancy.

The α-emitter astatine-211 targeted to CD38 can eradicate multiple myeloma in a disseminated disease model

AbstractMinimal residual disease (MRD) has become an increasingly prevalent and important entity in multiple myeloma (MM). Despite deepening responses to frontline therapy, roughly 75% of MM patients never become MRD-negative to ≤10−5, which is concerning because MRD-negative status predicts significantly longer survival. MM is highly heterogeneous, and MRD persistence may reflect survival of isolated single cells and small clusters of treatment-resistant subclones. Virtually all MM clones are exquisitely sensitive to radiation, and the α-emitter astatine-211 (211At) deposits prodigious energy within 3 cell diameters, which is ideal for eliminating MRD if effectively targeted. CD38 is a proven MM target, and we conjugated 211At to an anti-CD38 monoclonal antibody to create an 211At-CD38 therapy. When examined in a bulky xenograft model of MM, single-dose 211At-CD38 at 15 to 45 µCi at least doubled median survival of mice relative to untreated controls (P < .003), but no mice achieved complete remission and all died within 75 days. In contrast, in a disseminated disease model designed to reflect low-burden MRD, 3 studies demonstrated that single-dose 211At-CD38 at 24 to 45 µCi produced sustained remission and long-term survival (>150 days) for 50% to 80% of mice, where all untreated mice died in 20 to 55 days (P < .0001). Treatment toxicities were transient and minimal. These data suggest that 211At-CD38 offers the potential to eliminate residual MM cell clones in low-disease-burden settings, including MRD. We are optimistic that, in a planned clinical trial, addition of 211At-CD38 to an autologous stem cell transplant (ASCT) conditioning regimen may improve ASCT outcomes for MM patients.

Measurement of the DNA alkylating agents busulfan and melphalan in human plasma by mass spectrometry

Busulfan and melphalan are cytotoxic DNA alkylating agents that are used in many hematopoietic stem cell transplantation (HCT) conditioning regimens. We report the development of an assay using turbulent flow liquid chromatography (TFLC) and tandem mass spectrometry to simultaneously measure the concentration of busulfan (Bu) and melphalan (Mel) in human plasma. The method involves precipitating proteins in the plasma specimen with an organic solvent containing deuterated internal standards of both compounds. Following centrifugation, an aliquot of the supernatant was injected into the TFLC mass spectrometry system operated in the positive ion mode. The analytical measurement range for both compounds was 10–5000 ng/mL, and with validated dilutions the reportable range was extended to 25,000 ng/mL. Intra-day and inter-day (n = 20 day) precision studies showed a coefficient of variation (CV) of <7% at several concentrations across the measurement range. To determine accuracy recovery studies were performed at several concentrations spanning the measurement range. Recoveries for both compounds were between 98 and 103%. Additionally, busulfan was compared with an existing assay and showed excellent correlation. Experiments were conducted to rule out matrix effects, carryover and interference from endogenous substances. The validated clinically reportable range (CRR) and assay precision will allow this assay to be used clinically to monitor and adjust Mel and Bu levels to ensure better therapeutic outcomes and also to support clinical trials aimed at better defining therapeutic ranges.

Effect of intensification of induction II chemotherapy and liberalization of stem cell donor source on outcome for children with high risk acute myeloid leukemia: A report from the Children’s Oncology Group.

10002 Background: Patients with residual acute myeloid leukemia (AML) after induction fare poorly. The recently completed AAML1031 Phase III clinical trial intensified Induction II chemotherapy, altered the stem cell transplant (SCT) conditioning regimen, and liberalized SCT donor source criteria. We sought to test whether these practice changes improved clinical outcomes. Methods: Patients on AAML0531 and AAML1031, sequential Phase III trials for AML with shared high risk features of both &gt; 15% residual blasts by morphology and ≥ 0.1% minimal residual disease (MRD) by flow cytometry with uninformative cytogenetics or high risk cytogenetic features (-7 or -5/5q-) were included. Gemtuzmab exposed and patients with high allelic ratio FLT3 ITD were excluded. Patients were observed from the start of Induction II through last available follow up. Induction II chemotherapy (ADE or AraC/Mito) was the exposure of interest. Disease free and overall survival (DFS, OS) were the primary outcomes. Standard descriptive statistics were used to compare patient characteristics and secondary outcomes; Kaplan Meier analyses were used to evaluate DFS/OS. Results: A total of 47 patients from AAML0531 (ADE) and 95 patients from AAML1031 (AraC/Mito) were included and did not differ in baseline characteristics. Five year DFS ±2SE was 17.5 ± 11.4 for ADE and 23.9 ± 8.8 for AraC/Mito, p = 0.528. Five year OS was 38.1 ± 14.2 for ADE and 33.3 ± 10.7 for AraC/Mito, p = 0.364. End of Induction II disease response and MRD did not differ between ADE and AraC/Mito. Patients receiving ADE had a higher probability of neutrophil recovery (74% vs 53%, p = 0.019) and recovered neutrophils a median of 7 days more quickly (27 vs 34 days), p = &lt; 0.001. ADE patients also had fewer inpatient hospital days (28 days versus 32 days, p = 0.002). The percentage of patients receiving SCT did not differ, 34% vs 44%, p = 0.253 and post-SCT outcomes did not differ. Conclusions: The intensification of Induction II chemotherapy, change in SCT conditioning regimen, and liberalization of SCT donor source was not associated with improved clinical outcomes. Intensification of Induction II was associated with increased hematologic toxicity and length of stay. These data do not support the intensification of Induction II chemotherapy with AraC/Mitoxantrone. Clinical trial information: NCT01371981.

Otolog periferik kan kök hücre transplantasyonu sonrası mobilizasyon başarı oranı

Aim: If there issuccessful mobilization following a conditioning regimen forstem cell transplantation, the in vivo purged stem cell products may be collected for a second transplantation. Materials and Methods: In this prospective study, peripheral blood CD34+ cells were quantified between 6 th day after stem cell infusion and 3 rd day after neutrophil engraftment in 20 patients using flow cytometry. Results: In the autologous peripheral blood stem cell transplantation (auto-PBSCT)group(n= 16), the CD34+ cell count was lowest during the first 10 days. The median CD34+ cell count began to increase at the 11 th day and the highest value was achieved at the 14 th day. We documented evidence of mobilization in only one patient (6.25%). Conclusion: Our results indicate thatthe rate of successful stem cell mobilization is very lowfollowing auto-PBSCT. In conclusion, collecting CD34+ stem cells following the first auto-PBSCT is not an effective method for tandem transplantation.

Cyclophosphamide (Cy) pharmacogenetics (PGx) in allogeneic stem cell transplant (SCT) patients (pts) receiving Cy, fludarabine, total body irradiation and post-transplant Cy (FluCyTBI-postCy).

7058Background: Cy is the backbone for many SCT conditioning regimens and is used post-SCT to prevent graft vs. host disease (GVHD). It has been proposed that genetic polymorphisms impact Cy exposu...